Chemo- and Enantioselective Oxidative α-Azidation of Carbonyl Compounds

Article abstract of DOI:10.1002/anie.202007552

We report high-performance I⁺/H₂O₂ catalysis for the oxidative or decarboxylative oxidative α-azidation of carbonyl compounds by using sodium azide under biphasic neutral phase-transfer conditions. To induce higher reactivity especially for the α-azidation of 1,3-dicarbonyl compounds, we designed a structurally compact isoindoline-derived quaternary ammonium iodide catalyst bearing electron-withdrawing groups. The nonproductive decomposition pathways of I⁺/H₂O₂ catalysis could be suppressed by the use of a catalytic amount of a radical-trapping agent. This oxidative coupling tolerates a variety of functional groups and could be readily applied to the late-stage α-azidation of structurally diverse complex molecules. Moreover, we achieved the enantioselective α-azidation of 1,3-dicarbonyl compounds as the first successful example of enantioselective intermolecular oxidative coupling with a chiral hypoiodite catalyst.

Full text of DOI:10.1002/anie.202007552

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Chemo- and Enantioselective Oxidative α-Azidation of Carbonyl
Compounds
Authors: Muhammet Uyanik, Naoto Sahara, Mayuko Tsukahara, Yuhei
Hattori, and Kazuaki Ishihara
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202007552
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10.1002/anie.202007552
Angewandte Chemie International Edition
RESEARCH ARTICLE
a
Chemo- and Enantioselective Oxidative -Azidation of Carbonyl
Compounds
Muhammet Uyanik, Naoto Sahara, Mayuko Tsukahara, Yuhei Hattori, Kazuaki Ishihara*
In the memory of Prof. Dr. Kilian Muñiz
[*]
Prof. Dr. M. Uyanik, Dr. N. Sahara, M. Tsukahara, Y. Hattori, Prof. Dr. K. Ishihara
Graduate School of Engineering
Nagoya University
Chikusa, Nagoya, 464-8603 Japan.
E-mail: ishihara@cc.nagoya-u.ac.jp
Supporting information for this article is given via a link at the end of the document.
Abstract: We report a high-performance I+/H2O2 catalysis for the
oxidative or decarboxylative oxidative a-azidation of carbonyl
compounds by using sodium azide under biphasic neutral phase
transfer conditions. To induce higher reactivity especially for the a-
azidation of 1,3-dicarbonyls, we designed a structurally compact
isoindoline-derived quaternary ammonium iodide catalyst bearing
(Scheme 1a, left).[8] Recently, oxidative umpolung a-azidation
reactions have also been developed using iodine-based
catalysis.[9–13] For instance, in 2012, Kirsch and colleagues first
achieved
the
hypoiodite-catalyzed
oxidative[9a]
or
decarboxylative[9b] oxidative a-azidation of 1,3-dicarbonyls by
using sodium azide in the presence of a catalytic amount of
electron-withdrawing groups.
In addition, the non-productive
sodium iodide (Scheme 1b).
However, to induce high
decomposition pathways of I+/H2O2 catalysis could be suppressed by
the use of a catalytic amount of a radical trapping agent. This
oxidative coupling tolerates a variety of functional groups and could
be easily applied to the late-stage a-azidation of structurally diverse
complex molecules. Moreover, we achieved the enantioselective a-
azidation of 1,3-dicarbonyls, as the first successful example of
enantioselective intermolecular oxidative coupling using chiral
hypoiodite catalysis.
chemoselectivity, stoichiometric amount of IBX-SO3K, a
a
sulfonylated derivative of 2-iodoxybenzoic acid (IBX), was
required as an oxidant, and organic wastes derived from the
oxidant were generated. The same research group has also
developed a simpler and practical method using a stoichiometric
amount of molecular iodine instead of hypervalent iodine
reagents,[9] however, it suffered a bit from the limited substrate
scope and chemoselectivity.[9a]
required an excess amount of sodium azide under highly polar
conditions in aqueous dimethyl sulfoxide.[9]
During our
In addition, both methods
investigation,[10] oxidative azidation of 1,3-dicarbonyl compounds
using hypoiodite/(H2O2 or TBHP) catalysis was reported. Prabhu
and colleagues reported an a-azidation reaction using TBHP as
Introduction
Organic azides have been widely used in organic synthesis as a
masked amino group or a precursor of the highly reactive
intermediates such as nitrenes or iminophosphoranes.[1]
Especially, after the invention of “click” chemistry,[2] organic
azides have become some of the most popular and important
classes of organic compounds as versatile building blocks in
various disciplines including chemical biology, pharmaceutical
and material sciences.[1,3] Among them, a-azido carbonyls
bearing an electron-withdrawing oxo functionality at the adjacent
position have received considerable attention because of their
unique chemical behaviors and synthetic potential compared to
simple alkyl azides.[4,5] In addition, a-azido carbonyls could be
readily converted to various heterocycles such as triazoles or
imidazole carbonyls, oxazoles, pyrroles, pyridines, pyrazines,
an oxidant in the presence of
a
catalytic amount of
However,
tetrabutylammonium iodide (Scheme 1c).[11]
trimethylsilyl azide (TMSN3) as an expensive and volatile azide
source was used under harsh conditions (80 °C). On the other
hand, Nagasawa[12] and Waser[13] independently reported room-
temperature oxidative azidation protocols using hydrogen
peroxide or its urea complex (urea hydrogen peroxide, UHP) as
an oxidant (Scheme 1d). However, these methods also required
TMSN3 as an azide source. In addition, generally, the best results
were obtained for the reaction of highly reactive cyclic 1,3-
dicarbonyl compounds.
Despite their great utility in organic chemistry and many other
disciplines, organic azides are energy-rich molecules that are
recognized as heat- and shock-sensitive and potentially explosive.
tetrazoles and oxadiazoles.[4,6]
Especially, a-1,2,3-triazole
[1]
Therefore, these compounds should be prepared and used
carbonyls prepared from the corresponding a-azido carbonyls
have recently received particular attentions as bioisosteres of
amide bonds for the development of peptidomimetics.[7]
Conventionally, a-azido carbonyl compounds are synthesized by
nucleophilic substitution of a-halo or a-sulfonyloxy compounds
with an azide anion (Scheme 1a, right).[4] Direct electrophilic a-
azidation of carbonyls or their enol derivatives has also been
reported, however, expensive and potentially explosive tosyl
azide or hypervalent iodine-based reagents are often required
under mild conditions as much as possible. In particular, safe and
easy-to-handle azide sources and reagents should be used only
in the minimum required quantities for their preparation. In
addition, given their potential applications, especially in chemical
biology, the development of a general protocol for a late-stage
direct a-azidation of carbonyl functionality in structurally complex
molecules is desired.[1,4,14] Considering these issues, NaN3 would
be preferred as an ideal azide source because it is very
inexpensive, atom economical, and one of the safest inorganic
1
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10.1002/anie.202007552
Angewandte Chemie International Edition
RESEARCH ARTICLE
azides, and is used to prepare most common azides, including
TMSN3.[1a,15] In addition, with respect to atom- and step-
economy,[16] an oxidative umpolung strategy would be preferred
for the direct a-azidation of carbonyls with NaN3.[4] Here, we
report a high-performance hypoiodite catalysis[17,18] for the
chemoselective oxidative or decarboxylative oxidative a-azidation
of 1,3-dicarbonyls or b-oxocarboxylic acids, especially late-stage
azidation of complex molecules using NaN3 and hydrogen
peroxide as an azide source and oxidant, respectively, under very
mild conditions (Figure 1e).
moderate yield after 12 h with the use of 5 mol% of
tetrabutylammonium iodide (3a) as a catalyst. To improve the
reaction rate, we explored a new quaternary ammonium cation of
catalyst. Structurally compact and easily available (two-step
synthesis) isoindoline-derived 3b bearing electron-withdrawing
groups showed excellent catalytic activity, and 2a was obtained
quantitatively after a reaction time of only 1 h. To understand the
structural and electronic influence of the ammonium cation, 3c,
which is not derived from isoindoline but bears electron-
withdrawing groups, was examined and found to exhibit higher
activity than 3a, but lower activity than 3b. On the other hand, 3d,
which is derived from isoindoline but does not bear electron-
withdrawing groups, showed reactivity similar to that of 3a. These
results indicate that both structurally compact and electronically
deficient features of 3b might be crucial to induce high catalytic
activity.
a) Conventional methods:
O
O
O
–
TsN3 or ArI(III)–N3
electrophilic
N3
H
N3
R3
R2
LG
R3
R1
R2
R1
R1
nucleophilic
R3
R2
pre-functionalized
(LG = Halogen or OSO3R)
expensive and potentially explosive reagents
Oxidative umpolung methods using iodine-based catalysis:
b) Kirsch et al.[9]
O
O
O
O
3 (5 mol%)
30% H2O2 (2 equiv.)
HO
O
O
• organoiodine(V) as an oxidant
• organic waste derived from oxidant
• excess NaN3
• high-polar solvent
I
OMe
+ NaN3 (1.2 equiv.)
OMe
N3
H
1a
MTBE/H2O, 25°C
KO3S
2a
O
I–
N+
I–
I–
I–
N+
oxidant (1.5 equiv)
NaI (20 mol%)
O
O
O
O
O
O
O
ArF
ArF
ArF
ArF
nPr
nPr
nPr
nPr
nPr
nPr
nPr
N3
N+
N+
R1
OR3 R1
R1
OR3 R1
OH
R4
nPr
R2
NaN3 (3–10 equiv)
DMSO/H2O, RT–60 ºC
H
R4
R2
R2
R2
N3
3a, 54% (12 h)
3b, 97% (1 h)
95% isolated yield
3c, 97% (4 h)
3d, 55% (12 h)
a complementary stoichiometric system: I2 (>1.5 eq.) + NaN3 (excess)
100
3b
3c
c) Prabhu et al.[11]
Bu4NI (10 mol%)
TBHP (2 equiv)
O
O
O
O
75
50
25
R1
OR3
R1
OR3
CF3
TMSN3 (2 equiv)
H2O, 80 ºC
• expensive & volatile N3 source • high danger temperature
R2
R2
3d
3a
N3
H
ArF
=
CF3
d) Nagasawa et al.[12], Waser et al.[13]
R4NI (10 mol%)
UHP or 30% H2O2 (1.2 equiv)
O
O
O
O
OR3
OR3
N3
TMSN3 (2 equiv)
Toluene or CH3CN, RT
0
0
H
4
8
12
time (h)
• limitied to highly reactive substrates • expensive & volatile azide source
e) This work: High-performance I+/H2O2 catalysis for oxidative α-azidation
Scheme 2. a-Azidation of cyclic b-oxoester 1a as a highly reactive substrate
CF3
I–
CF3
N+
or Bu4NI
cat.
Next, we examined the a-azidation of acyclic 1b as a poorly
reactive substrate (Table 1, for details see Table S1). However,
desired 2b was obtained in 18% yield along with a considerable
amount of a-diazido compound 2b’ (Table 1, entry 1), which was
presumably obtained via decarboxylative over-azidation in a
reaction medium that would be strongly alkaline due to the
generation of sodium hydroxide from NaN3 as the reaction
proceeds (Figure 1a). This side-reaction could be suppressed by
using a pH 7 buffer as a co-solvent. However, the reaction rate
was also decreased under these neutral conditions, and, most
importantly, the reaction stopped at low conversion (Table 1, entry
2). To establish a high-performance I+/H2O2 catalysis, we
reconsidered the general catalytic mechanism of hypoiodite
catalysis (Figure 1a). Ammonium hypoiodite would be readily
generated in situ as an unstable catalytic active species from
tetraalkylammonium iodide and hydrogen peroxide or alkyl
hydroperoxide (TBHP or CHP) as an oxidant.[18a] When the
desired oxidative coupling reaction is slow, triiodide I3– as a stable
inert species would be generated when an alkyl hydroperoxide is
used as an oxidant.[17b] On the other hand, when hydrogen
peroxide was used as an oxidant for challenging reactions, the
CF3
CF3
30% H2O2
NaN3 (1.2 equiv)
O
O
O
O
O
O
O
N3
R4
R1
R3 R1
R1
R3 R1
OH
MTBE/pH 7 Buffer
Room Temperature
R2
R4
R2
R2
R2
N3
H
· designer catalyst (compact and e-deficient)
· highly chemoselective (a wide-range of FG tolerance)
· applied to enantioselective α-azidation
Scheme 1. Previous methods and this work for a-azido carbonyls.
Results and Discussion
We commenced our investigation by examining the a-azidation of
b-oxoester 1a using a 30% aqueous solution of hydrogen
peroxide and NaN3 as an oxidant and azide source, respectively,
under phase-transfer conditions by using a mixed solvent of
methyl tert-butyl ether (MTBE) and water at room temperature
(Scheme 2). However, the desired product 2a was obtained in
2
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10.1002/anie.202007552
Angewandte Chemie International Edition
RESEARCH ARTICLE
catalytic oxidative decomposition[19–21] of hydrogen peroxide to
water and oxygen gas would proceed preferentially. In fact, the
reaction proceeded further with additional hydrogen peroxide
(Table 1, entry 3, and Figure S1), which reflected undesired
decomposition of the oxidant used.
NaN3
a)
R4N+IO–
H2O
1
H2O2
non-productive
path
In our previous study, the non-productive pathways of I+/ROOH
catalysis (i.e., generation of I3– inert species) could be suppressed
by using inorganic base additives, and high-performance
I+/ROOH catalysis has been established.[17b] However, no
efficient strategy has yet been reported to suppress
nonproductive pathways (i.e., oxidative decomposition of oxidant)
for I+/H2O2 catalysis, although the use of hydrogen peroxide is
highly preferable because it is less expensive and more atom-
economical than alkyl hydroperoxide.[22] Because the oxidative
decomposition of hydrogen peroxide might involve radical
intermediates,[20,23] and the present oxidative coupling reaction
might proceed via an ionic mechanism, we found that the non-
productive pathways of I+/H2O2 catalysis could be suppressed by
using a catalytic amount of a radical trapping agent such as a-
phenyl-N-tert-butylnitrone (PBN) or 5-(diethoxyphosphoryl)-5-
methyl-1-pyrroline N-oxide (DEPMPO) (Table 1, entries 4 and 5,
for further investigation of additives, see Table S1). Notably, in
comparison with the striking results using catalyst 3b shown in
entry 4, unreacted 1b was almost recovered with the use of
catalysts 3a, 3c and 3d under the same mild conditions (Table 1,
entry 6). EPR analysis revealed that the hydroxyl radical
generated as a key intermediate for a decomposition pathway
might be trapped by DEPMPO (Figure 1b and Figure S2).[24] We
anticipate that these findings will lead to new concepts for the
development of high-performance redox catalysis that use
hydrogen peroxide as an oxidant.
O2 + H2O
H2O2
R4N+I–
2
NaOH
(neutralized with pH 7 Buffer)
b)
30% H2O2 + DEPMPO
O
P(OEt)2
3a
HO
N
O
Figure 1. (a) Mechanistic consideration of I+/H2O2 catalysis. (b) Experimental
(black) and simulated (red) EPR spectrum of the trapped radical, DEPMPO-OH,
[24] during the oxidative decomposition of hydrogen peroxide in the presence of
For details, see the Supporting Information.
(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide.
3a.
DEPMPO, 5-
The chemoselective oxidative a-azidation of a wide range of 1,3-
dicarbonyls 1, including b-oxoesters, 1,3-diketones and 1,3-
diesters proceeded smoothly under the optimized conditions, and
desired products 2 could be obtained in high yields (Scheme 3a).
A wide range of different functional groups such as halo,
(poly)alkenyl, heteroaryl, cyclopropyl, hydroxy, formyl, amino and
acetal groups were tolerated under these mild conditions. In
addition, the oxidative coupling of steroidal substrates 1w and 1x
gave the corresponding a-azides with good diastereoselectivity
(9:1 d.r.), which was confirmed by X-ray analysis of the
Table 1. Investigation of the oxidative a-azidation of linear b-oxoester 1b as a
poorly reactive substrate.
3b (5 mol%)
30% H2O2 (1.5 equiv.)
NaN3 (1.2 equiv.)
O
O
O
O
O
N3
N3
+
OMe
Ph
Ph
OMe
Ph
additive (20 mol%)
MTBE/co-solvent
25°C, 11 h
N3
1b
2b
2b’
Entry
1
Co-solvent
H2O
Additive
–
Yield, 2b (%)[a]
Yield, 2b’ (%)[a]
corresponding [3+2]-adduct
4
derived from the major
18
26
<1
<1
<1
7
diastereomer of 2w. On the other hand, as expected,[4a,9c]
selective a-monoazidation of the a-nonsubstituted 1,3-
dicarbonyls was not feasible due to the higher reactivity of the
monoazide intermediates. Instead, the corresponding a,a-
diazides 2t–v were obtained in high yield. Notably, these
reactions proceeded chemoselectively under slightly acidic
conditions (pH 4.3) by using an aqueous solution of NaH2PO4
instead of pH 7 buffer to prevent the decomposition[4a,5] of the
monoazide intermediates (Table S2). Most importantly, our a-
azidation protocol could be applied successfully to the late-stage
a-azidation of several structurally diverse complex medicinally
relevant compounds (Scheme 3b). These structurally complex
1,3-dicarbonyl derivatives 1y–ag could be easily prepared in one-
step from the corresponding carboxylic acid-containing drugs by
the Masamune reaction.[25] Given the abundance of alkyl
carboxylic acids in natural products and drug molecules, we
anticipate that, by combining with Masamune reaction, this
protocol could provide a new opportunity to access previously
difficult-to-access medicinally relevant a-azido carbonyls.[26]
2
pH 7 Buffer
pH 7 Buffer
pH 7 Buffer
pH 7 Buffer
pH 7 Buffer
–
37
3[b]
4
–
81
PBN
97 (94)[c]
87
5[d]
6[e]
DEPMPO
PBN
<5
<1
[a] Yields were determined by 1H NMR analysis. [b] After 7 h, 30% H2O2 (1
equiv.) was added. [c] Isolated yield. [d] 30% H2O2 (1.3 equiv.). [e] Catalyst
3a or 3c or 3d was used instead of 3b. For details, see the Supporting
Information.
PBN,
a-phenyl-N-tert-butylnitrone;
DEPMPO,
5-
(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide.
O
t-Bu
P(OEt)2
Ph
N
O–
N
O–
PBN
DEPMPO
3
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10.1002/anie.202007552
Angewandte Chemie International Edition
RESEARCH ARTICLE
3b (5 mol%)
30% H2O2 (1.5 equiv.)
O
O
O
O
+
NaN3 (1.2 equiv.)
R1
R3
R1
R3
R2
PBN (20 mol%)
MTBE/pH 7 Buffer, 25°C
R2
H
N3
2
1
R1, R2 = 4-Me, Me (2c): 87%
4-MeO, Et (2d): 89%[a]
4-F, Et (2e): 83%
O
O
O
O
O
O
O
O
O
O
Ph
O
O
S
OR2
OMe
OEt
Ph
OtBu
OEt
R1
OMe
N3
N3
N3
N3
N3
N3
( )n
2-F, Me (2f): 83%
2h: 87%
n = 1 (2i): 93%
2 (2j): 93%[a]
2k: 67%[b]
2l: 95%[c]
2m: 91%
4-CHO, Et (2g): 52%
O
O
OH
O
O
O
O
O
O
O
O
O
O
X
OEt
OEt
OEt
OEt
Ph
Ph
Ph
H
OtBu
N3
N3
N3
N3
N3
N3 N3
X = Cl (2n): 83%[c]
Br (2o): 91%[c]
2r: 90%
2s: 85%
2t: 71%[d]
2p: 81% (d.r. 1:1)
2q: 89%
O
O
O
O
4-BrC6H4C≡CH
O
O
O
O
H
OMe
OMe
N3
N3
BocHN
EtO
OEt
OtBu
[3+2] click
H
H
H
H
N3 N3
N3 N3
2v: 82%[d]
estrone
androstenolone
HO
HO
2u: 87%[d]
2w: 81% (d.r. 9:1)[c][e]
2x: 90% (d.r. 9:1)
4
O
O
O
O
O
O
O
O
CDI, MgCl2
azidation
as above
O
+
OR3
R1
OR3
R1
OR3
KO
R1
OEt
OEt
OH
Masamune reaction
2 N3
2 H
R2
R
R
N3
retinoic acid
drug molecules
1
2
2y: 81%
O
N
O
O
Cl
O
O
OMe
O
F
O
O
O
OEt
OEt
O
O
N
NH
O
O
N3
N3
O
N
Cl
O
OEt
N3
OH
BocN
N3
ciprofloxacin
2z: 60%[e]
acemetacin
mycophenolic acid
O
OMe
Cl
aceclofenac
2ab: 71%
2ac: 87%
2aa: 69%
H
artesunate
2ag: 78% (1.1 gram)[d]
O
O
O
O
O
O
O
O
O
O
O
Cl
NH
H
OEt
H
H
O
O
OEt
N3
HN
OEt
N3
O
O
Ph
N3
N
S
H
O
O
OtBu
oxaprozin
2ad: 76% (1.1 gram)
fenofibric acid
2ae: 42% (70% of BRSM)[e]
biotin
Ph
N3 N3
2af: 79% (d.r. 1:1)[e]
O
Scheme 3. (a) Chemoselective oxidative a-azidation of various 1,3-dicarbonyls 1. (b) Late-stage oxidative a-azidation of structurally complex molecules 1. Unless
otherwise noted, the reactions were performed with 0.1–0.2 mmol of 1, and the isolated yields of 2 from 1 are reported. 1y–ag were synthesized form the
corresponding drug molecules in one step (Masamune reaction). For details, see the Supporting Information. [a] 30% H2O2 (2 equiv.) was used. [b] Yield was
determined by 1H NMR analysis. [c] 30% H2O2 (3 equiv.) was used. [d] NaN3 (2.4 equiv.) and 30% H2O2 (3 equiv.) were used for diazidation. In addition, NaH2PO4
aq. was used instead of pH 7 buffer. [e] EtOAc was used instead of MTBE at 40 °C to enhance solubility. Boc, tert-butyloxycarbonyl; CDI, 1,1'-carbonyldiimidazole;
BRSM, based on recovered starting material.
As in the previously reported catalytic oxidative methods,[9–13] our
protocol could not be applied to the oxidative a-azidation of
monocarbonyls. Alternatively, we developed the hypoiodite-
catalyzed decarboxylative[27] a-azidation[9b] of b-oxocarboxylic
acids or malonic acid monoesters to give the corresponding a-
azido monocarbonyls (Scheme 4, for details see Table S3).
Decarboxylative functionalization of b-oxocarboxylic acids has
been widely used in various synthetic protocols because of the
ease of releasing carbon dioxide under mild conditions to
generate the corresponding enolates in a site-specific fashion.[28]
Decarboxylative azidation of b-oxocarboxylic acid 5a under
conditions that were optimized for 1,3-dicarbonyls 1 using catalyst
3b gave a complex mixture of the desired monoazide 6a in only
20% yield along with triazide 7a and protonated product 8a in 21%
and 45% yields, respectively (Scheme 4, entry 1). Notably, the
use of PBN to prevent the decomposition of hydrogen peroxide
was unnecessary (vide infra). On the other hand, control
experiments using 5a in the absence of NaN3 and oxidant
revealed that the decarboxylation reaction might be catalytically
accelerated by quaternary ammonium salts, and decarboxylative
protonation proceeded much faster to give 8a with the use of 3b
(Table S4). Therefore, the rate of the decarboxylation process
should be reduced by the use of a less-reactive catalyst to avoid
the competitive undesired protonation reaction. To this end, we
achieved a chemoselective decarboxylative monoazidation of 5a
by using 3a to give desired 6a in 94% yield (Scheme 45, entry 2).
Notably, in contrast to Kirsch’s method,[9b] both monoazide 6a and
geminal triazide 7a could also be synthesized selectively by the
controlling the amounts of reagents used under these mild
conditions (Scheme 4, entry 3).
4
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10.1002/anie.202007552
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RESEARCH ARTICLE
cat. (x mol%)
30% H2O2 (1.2 equiv.)
NaN3 (1.2 equiv.)
To gain mechanistic insight into (decarboxylative) oxidative a-
azidation, we performed several control experiments (Scheme 6.
For details, see the Supporting Information). The reaction of b-
oxoester 1b or b-oxocarboxylic acid 5a using a stoichiometric
amount of respective quaternary ammonium iodide 3b or 3a gave
the corresponding a-iodo adduct 9b or decarboxylated a-iodo
adduct 10a, respectively, which then underwent nucleophilic
substitution with NaN3 to afford the corresponding a-azido
carbonyls 2b or 6a (Schemes 6a and 6b). These results indicate
that a-iodo carbonyls[9] might be a key intermediate for the
(decarboxylative) oxidative azidation reactions. Notably, the use
of ammonium iodide 3b instead of 3a for the decarboxylative
oxidative a-iodination of 5a gave an equimolar mixture of 10a and
protonation product 8a that is consisted with the Scheme 4 in
which highly reactive 3b led to the undesired competitive path
O
O
O
O
O
N3
N3
+
+
Ph
Ph
Ph
Ph
OH
MTBE/pH 7 Buffer
25°C, 5 h
N3
N3
H
5a
entry cat. (mol%)
6a (%)
7a (%)
21
8a (%)
45
1
2
3
3b (5)
20
94
<1
3a (20)
3a (20)
2
80[a]
1
<1
Scheme 4. Investigation of chemoselective decarboxylative oxidative a-
azidation of b-oxocarboxylic acid 5a. [a] NaN3 (3.6 equiv.) and H2O2 (6.5 equiv.)
were used for 36 h.
Oxidative decarboxylative a-azidation of a wide range of b-
oxocarboxylic acids
5 including structurally complex drug
(Scheme 6b).
In addition, substitution reaction of a-iodo
derivatives (5l–p) under the optimized conditions gave the
corresponding monoazides 6 in good to high yields (Scheme 5).
Notably, the decarboxylative azidation reaction proceeded even
with a-disubstituted b-oxocarboxylic acids 5e–g and 5n including
a-fluoro derivatives, which have been reported only rarely,[29] to
give the corresponding a-quaternary azido carbonyls 6 in good
yields. In addition, the reaction of these a-disubstituted b-
oxocarboxylic acids as well as malonic acid monoesters were
performed in the absence of pH 7 buffer to accelerate both the
decarboxylation process and the nucleophilic substitution of the
a-iodo intermediate (vide infra) with an azide anion (For details,
see Table S6).
carbonyls with an azide anion was too slow in the absence of
ammonium salt catalysts under phase-transfer conditions. Note
that despite the observations of these a-iodo compounds 9 or 10
as
a relatively stable and isolable intermediates, O-vinyl
hypoiodite intermediates could not completely rule out to give the
a-azido products via SN2’ type addition of ammonium azide. On
the other hand, based on the control experiments (Table S8), in
situ generated I+ species such as hypoiodite might be the catalytic
active species for the present oxidative a-azidation reactions, as
in our previous oxidative coupling reactions.[19,20,23] Based on
these results, a proposed catalytic mechanism is depicted in
Scheme 6c, which consists of three main steps: oxidation of
iodide to the hypoiodite active species, (decarboxylative) a-
iodination of
corresponding a-iodo intermediate 9 or 10.
1 or 5, and nucleophilic azidation of the
3a (20 mol%)
30% H2O2 (1.2 equiv.)
O
O
O
N3
R3
+
NaN3 (1.2 equiv.)
OH
O
R1
O
R1
MTBE/pH 7 Buffer
25°C
R2 R3
R2
6
5
a)
3b (1 equiv.)
30% H2O2 (1.5 equiv.)
3b (10 mol%)
NaN3 (1 equiv.)
O
O
O
O
O
O
N3
N3
N3
Ph
N3
Ph
Ph
1b
Ph
OMe
Ph
OMe
R
MTBE/pH 7 Buffer
25°C, 8 h
MTBE/pH 7 Buffer
25°C, 2 h
F
N3
I
R
R = Me (6f): 88%[a]
6d: 81%
6e: 84%[a]
R = MeO (6b): 89%
Cl (6c): 70%
9b: 85%
2b: 75%
Et (6g): 81%[a]
cf. with 3a, 9b: <1%
(1b: >95% recovered)
O
O
O
O
N3
b)
MeO
Ph MeO
N3
3a (1 equiv.)
3a (20 mol%)
Ph
H
N3
N3
30% H2O2 (1.5 equiv.)
NaN3 (1 equiv.)
O
O
HN
6j: 78%[a]
6h: 64%[b]
6i: 90%
6k: 86%[a]
5a
I
N3
Ph
10a: 90%
Ph
MTBE/pH 7 Buffer
25°C, 1 h
MTBE/pH 7 Buffer
25°C, 4 h
O
O
O
6a: 95%
N3
EtO
cf. with 3b, 8a: 50%, 10a: 50%
cf. w/o 3a (24 h), 6a: <5%
(10a: >95% recovered)
OMe
O
H
H
N3
precursor of Aβ inhibitor
6m: 75%[a]
decholin
c)
6l: 78%[b]
O
O
H
N
O
H2O2
R4N+I–
2 or 6
O
azidation
(r.d.s. for 5)
oxidation
O
H2O
O
O
N3
N
Ph
NH
etodolac
6p: 70%[a]
N3
O
F
O
O
O
oxaprozin
6n: 56%[a][c]
isoxepac
N3
O
I
Ph
–
+ R4N+ N3
R4N+ IO–
R1
R3
6o: 51%
R1
R3
R2
R2
I
9 (from 1)
10 (from 5)
Scheme 5. Chemoselective decarboxylative oxidative a-azidation of various b-
oxocarboxylic acids 5, including structurally complex molecules. Unless
otherwise noted, the reactions were performed with 0.1 mmol of 5, and the
isolated yields of 6 are reported. [a] Buffer was not used to accelerate the
decarboxylation process. [b] EtOAc was used as an organic solvent instead of
MTBE to enhance solubility. [c] 3b was used instead of 3a.
iodination
(r.d.s. for 1)
NaOH
(to be buffered)
1 or 5 + NaN3
Scheme 6. Control experiments to probe reaction intermediates (a and b) and
proposed mechanism (c).
5
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10.1002/anie.202007552
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RESEARCH ARTICLE
To gain insight into the catalytic cycle of both oxidative a-azidation
reactions, we performed kinetic studies using the
(decarboxylative) azidation of 1b or 5a as model reactions. The
reaction rate of oxidative a-azidation of 1b was found to have first-
order dependence on the concentrations of both 1b and 3b, and
zero-order dependence on both NaN3 and hydrogen peroxide
(Figure S3). These results suggest that a-iodination or the initial
enolization might be the rate-determining step (r.d.s.) in the
catalytic cycle of the oxidative a-azidation of 1 (Scheme 6c).
Therefore, electrostatic or hydrogen-bonding interactions[30]
between the 1,3-dicarbonyl substrates (for the enolization step) or
leaving group of the I+ species (for the iodination step) and the
ammonium cation center or acidic a-hydrogen atoms of 3b,
respectively, might enhance the reactivity of the enolization or
iodination steps for 1,3-dicarbonyls 1. While a prominent H/D
exchange on the a-carbon of 1b was observed with the use of 3b
in deuterated pH 7 buffer, a very slow H/D exchange was
observed in the presence of 3a or the absence of catalyst,
indicating the facile enolization of 1,3-dicarbonyls with the use of
designer catalyst 3b (Figure S4). Nevertheless, although slow yet
feasible enolization of 1b was observed with 3a (Figure S4), an
oxidative a-iodination of 1b with a stoichiometric amount of 3a
instead of 3b gave no product 9b (Scheme 6a). In addition, the
reaction rate of 3b-catalyzed enolization of 1b was much faster
than that of the oxidative a-azidation reaction (Figure S5). These
results suggested that a-iodination rather than enolization might
be a rate-determining step for 1,3-dicarbonyls 1.
On the other hand, the reaction rate of decarboxylative a-
azidation of 5a was found to have first-order dependence on the
concentration of only 3a, and zero-order dependence on 5a, NaN3
and hydrogen peroxide (Figure S6), which suggested that
nucleophilic azidation of the a-iodo intermediates 10 might be the
rate-determining step for the decarboxylative a-azidation of 5
(Scheme 6c). Notably, these contrary results obtained from the
kinetics experiments were consistent with the control experiments
in which, while azidation was much faster than iodination for b-
keto ester 1b, iodination was faster than azidation for b-
oxocarboxylic acid 5a (Schemes 6a and 6b). In addition, a-iodo
intermediate 10a was clearly observed by in situ NMR analysis of
the decarboxylative azidation reaction of 5a (Figure S7), which
again was consistent with the kinetic studies. Compared to the
azidation of 10, a faster SN2-type azidation of a-iodo-1,3-
(Figure S10). By taking advantage of the catalytic mechanism
(Scheme 6c), in which nucleophilic azidation might proceed
smoothly after the rate-determining a-iodination step, we could
apply our chiral hypoiodite catalysis to the enantioselective a-
azidation of cyclic b-oxoesters 1 with NaN3 as an azide source by
using chiral binaphthyl-based quaternary ammonium iodide 3e[17]
(Scheme7, for details, see Table S7). Notably, the use of cumene
hydroperoxide (CHP) instead of hydrogen peroxide slightly
improved the enantioselectivity, especially at lower temperature
(0 °C). In addition, higher enantioselectivity was achieved under
slightly acidic conditions by using an aqueous solution of
NaH2PO4 (pH 4.3) instead of pH 7 buffer.[34] Enantioselective
oxidative a-azidation of indanone-derived cyclic b-oxoesters 1ah–
1ao proceeded smoothly to give the corresponding a-quaternary
azido compounds 2 with high enantioselectivity (83 to 88% ee).
In addition, cyclopentanone- and succinimide-derived b-
oxoesters 1ap and 1aq could also be used as substrates for the
present enantioselective oxidative azidation albeit with diminished
selectivity. The absolute configuration of products 2 was
assigned to be S by analogy to the literature.[33] As a control
experiment, a-hydroxylation[35] of 1ah with the use of the same
catalyst 3e, to make a similar chiral environment for the enolate
intermediate, in the absence of NaN3 gave the (R)-adduct with
84% ee (Figure S8), which indicated that nucleophilic azidation
might proceed in an SN2 manner with inversion of stereochemistry.
On the other hand, an SN1 or SN2X-type mechanism[36] might be
unlikely since azidation of a racemic a-iodo intermediate 9ah
derived from 1ah under the identical conditions gave rac-2ah
(Figure S9). Although the substrate scope is currently limited
mainly to indanone-derived cyclic b-oxoesters 1, this is the first
example
of
chiral
hypoiodite-catalyzed
intermolecular
enantioselective coupling reactions.
Ar
I–
N
Ar
O
O
O
O
3e (5 mol%)
CHP (1.5 equiv.)
OtBu
+ NaN3
(1.2 equiv.)
R
OtBu
Toluene/NaH2PO4 aq.
0°C, 24 h
N3
[a]
1
R = H (2ah):
4-Me (2ai):
90%, 85% ee
88%, 87% ee
73%, 88% ee
72%, 85% ee
87%, 84% ee
84%, 84% ee
86%, 87% ee
dicarbonyls
9 might be explained by stabilization of the
accumulated negative charge of the transition state by two
electron-withdrawing oxo groups. On the other hand, due to the
rapid consumption of hypoiodite species for the decarboxylative
a-iodination of b-oxocarboxylic acids 5, non-productive oxidative
decomposition of hydrogen peroxide could also be suppressed,
which might explain the lack of need for PBN in the
decarboxylative coupling reaction.
Finally, we were interested in the enantioselective a-azidation of
1,3-dicarbonyl compounds.[31] To the best of our knowledge, only
two enantioselective methods have been developed for the direct
enantioselective a-azidation of carbonyl compounds with
azidobenziodoxole[32] as a hypervalent iodine-based azide source
using transition metal[8c,33] or organocatalysis.[13] Mechanistic
consideration described above and in Supporting Information
revealed that, to render the reaction asymmetric, a-iodination step
4-OMe (2aj):
4-OTBS (2ak):
3-OMe (2al):
5-Ph (2am):
F3C
CF3
Ar in 3e =
CF3
CF3
3,4-(OCH O)- (2an):
2
O
O
O
O
O
O
HN
OtBu
OtBu
OtBu
N3
N3
N3
O
2ap: 69%, 66% ee
2aq: 73%, 61% ee
2ao: 88%, 83% ee
Scheme 7. Enantioselective oxidative a-azidation of 1,3-dicarbonyls. [a] 90%
yield, 82% ee with the use of 30% H2O2 instead of CHP. For details, see the
Supporting Information.
Conclusion
should proceed enantioselectively.
However, a-iodo
intermediates 9 were found to be stereolabile and readily
epimerized as could not be isolated in enantioenriched form
In conclusion, we have developed
ammonium hypoiodite/hydrogen peroxide
a
high-performance
catalysis for
6
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10.1002/anie.202007552
Angewandte Chemie International Edition
RESEARCH ARTICLE
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10.1002/anie.202007552
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
CF3
designer catalyst
I–
CF3
N+
CF3
O
O
O
O
CF3
30% H2O2
NaN3
R1
R3
R1
R3
2 N3
2 H
R
R
mild conditions at pH 7
O
O
O
N3
R3
OH
R1
R1
R2 R3
R2
A high-performance hypoiodite catalysis is developed for the chemoselective oxidative or decarboxylative oxidative a-azidation of
1,3-dicarbonyls, especially late-stage azidation of complex molecules using NaN3 and hydrogen peroxide as an azide source and
oxidant, respectively, under extremely mild conditions.
Institute and/or researcher Twitter usernames: @PIodide
9
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